Making the Move to Continuous Bioprocessing

Bioprocessing has taken on many forms over the years. Efficiency and process economics are driving the bioprocessing industry forward, fueling a move from traditional stainless steel to single use – and now continuous. 

We recently spoke to Martin Smith, CTO at Pall Corporation, to learn about the different types of bioprocess. Martin discusses the evolution of bioprocessing, touches on the benefits and factors to consider when adopting a continuous approach, and highlights the potential of continuous to enable new drug development innovations. 

Laura Mason (LM): Could you tell me a little more about your professional background, your role at Pall and the company’s mission and goals, with emphasis on how those relate to bioprocessing activities?

Martin Smith (MS): I'm the Chief Technology Officer at Pall with responsibility for R&D and new product development. I've been with Pall for twelve years and, as you know, Pall has been a Danaher operating company for three years. Danaher is a global science and technology innovator. Prior to Pall I was at GE Whatman. Most of my professional career has been in separation science, which involves the purification, isolation and clean-up of various items of value, whether that's a biological drug in bioprocessing, something within industrial manufacturing or the food and beverage industry. I have a PhD from University College London in biochemistry and cell biology. I currently reside in the US and I am based at Pall headquarters in Port Washington New York.

At Pall we are very much involved in separation science that includes: isolation, purification, concentration and enrichment of substances of value. There’s a broad range of industries that require that kind of capability – biotechnology being one of them.

You can imagine a bioreactor full of – let's call it junk – but within that junk is something of value – the biologic. The way users get that ‘item of value’, to an injectable place, a point of therapy, is through separation science. In terms of Pall’s mission, we provide innovative, integrated solutions to protect critical operating assets, improve product quality and safeguard health. Our company was founded on technological leadership and we have a leadership position in all industries we serve. We focus on those most valuable separation science capabilities – high value content that is changing the way in which our customer base is looking to serve their customer. For example, continuous and other types of bioprocessing approaches. How can filtration change and improve the way our customers think about their separation science needs? It's about taking our separation science core and pointing it directly at those most valuable applications that our customers are desperately looking to improve within their own work.

LM: Would you be able to elaborate on the different types of bioprocess available and how the process has evolved over the years?

MS: There are a lot of ways in which you can classify bioprocessing. At Pall we think about it in three ways – traditional stainless steel, single use technologies, and continuous process.

Stainless steel – the legacy types of drug discovery, drug development processes that we see consistently throughout the industry. Around 15 years ago we started to see stainless steel move into single use technologies. The industry began moving away from ‘the anchor’ of having to clean stainless steel over and over again and shifted to single use technologies.

More recently the evolution of single use moved in to the ability to run things continuously. Beyond continuous even—we may think about real-time release processes, but the industry isn't quite there yet.

At Pall we support stainless steel, single use and continuous. When it comes to continuous we can take a variety of approaches, we can think about end-to-end, single-use, modular types of factories, where we can bring all the unit operations and bolt them together and have a single train. Or we may think of this as continuously operating unit operations, the continuous chromatography skid, the continuous or perfusion bioreactor that's a certain batch type of operation and so on.

Customers are moving away from classic batch production. Efficiency and process economics are driving to fed-batch and then, ultimately, continuous culture. Perfusion culture is a way of continuously harvesting from the bioreactor rather than just waiting for it to grow, harvesting it in a single way, then jumping from step to step. That's the traditional way, now they are fed in a continuous way in which you harvest continuously and process continuously.

LM: Is there a specific type of bioprocessing that has garnered the most interest among experts?

MS: The bioprocessing community is always looking for advancement, whether that is in technology that will help them discover something more quickly or discover with more accuracy, or all the way through to factory process economics – they don't stand still. Right now, the industry is looking very squarely at how to cut down drug discovery or process development speed. “How do I cut my drug development cycle?”  And the onset of technologies like continuous is aimed directly at that dynamic – much faster development times, much more accurate and easy scale-up from laboratory bench to factory floor.

Customers then start to think about moving factories to enable bioprocessing at points of need. Pace, flexibility, process economics, these are the factors driving interest from our customer base. Our customers' customers are patients. What we do and how we enable our customers to be better, more flexible, less expensive and more accessible—which ultimately serves the patient, that's the key driver for all of this.

LM: What are the benefits of continuous bioprocessing?

MS: There are a lot of benefits, but ultimately there are three that go beyond the technology:

For the patient – Continuous bioprocessing and the greater accuracy through data analytics and monitoring, allows for higher concentrations of next generation biologics drug dosages, which will enable more personalized and effective medicines in potentially smaller/ less frequent administration and dosages. This could lead to increased drug effectiveness with fewer hospital admissions to receive treatment. The manufacturing process improves quality, through improved filtration, which can increase patient safety.

It can widen access to medicines by allowing for industrialization of drug manufacturing and integrated upstream and downstream processing. This builds on some of the “just in time” Kaizen processes, which have already transformed automotive manufacturing processes but have yet to be seen in drug manufacturing to date. It has the ability to deliver cheaper, better, more available drugs in the exact format a patient needs. The speed of production could help address drug shortages through faster, mass manufacture with higher quality yields. This can help with manufacturing “drugs on demand” around the world, using multiple locations closer to patient need, especially relevant in instances of new pandemics or emergencies. It’s really exciting.

Integrating technology can drive real change by enabling our customers – drug manufacturers – to explore ever more complex medicines and processes and apply cutting edge automation and robotic processes to explore ways to enable and deliver personalized medicines.

LM: Are there any particular challenges associated with adopting a continuous approach to bioprocessing?

MS: Every customer is going to have their own set of challenges – different drug classes, different types of biologic, vaccine, antibiotic and so on. But having said that, there are some fundamental things that come up repeatedly and the big one is managing requirements for regulatory bodies, such as the US Food and Drug Administration (FDA).

For example, how do you know you have not produced a ‘dud’ when you are running in a continuous mode? You press a button, you come back a week later to get your drug, so how do you know it is any good?

We are spending a lot of time, hand in hand with our customers, on committees with the FDA, to work out how process analytics are going to play into the continuous world.

• Where do we need to measure?  
• What do we need to measure?
• What does ‘good’ look like? 
• How can we manage excursion in a continuous mode? 

We're working through the FDA to address these questions. We don’t see it as a barrier to adoption, at least at the process development level, and our customers continue to work directly with the FDA. Process analytics and regulation are known considerations that we are acutely aware of and are working hand in hand with the FDA to establish specific requirements.

This is top of mind for our customers and we continue to work on strategies to address these new technologies and how best to approach the FDA.

It is a great source of information being part of those consortia.

LM: What impact has continuous bioprocessing made to drug development?

MS: We are in the emerging phase of continuous right now. The impact we have seen is evidenced by large adoption growth rates of certain continuous technologies. Biologic drug developers are largely taking their first steps in the journey to adopting continuous bioprocessing technologies through “process intensification” steps.

Process intensification is the focus right now, where can we bring clusters of unit operation steps together, compact them, unit operationalize them, in a continuous way so that we get greater and faster process economics. But another way that we are going to market on that front is we are offering, or will be offering, process development service to our customers. They can come to us with their drug candidates and we will then develop the end-to-end continuous process for them, as a service.

So, it's really a two-phased approach. Yes, we are seeing an impact right now, which is process intensification with our technologies, but when it comes to the end-to-end process, that will come over time, which will accelerate through our own process development.

LM: Could you touch on some of the continuous technologies that are being developed by Pall?

MS: As we go to market in continuous, we felt it was important to ensure we can occupy every single position of the downstream process with a continuous version. So that it is compatible with a continuous flow and can also operate at a scale version, a process development version, and full GMP factory scale.

Every single step of the downstream can now be served by Pall with a continuous compatible product, and we have versions that can work at the scale down and scale up positions, as we can operate between 50 litre and 2000 litre volumes.

Where we have seen the most movement and the most interest, is the chromatography step, the protein A step. This is where downstream process production professionals and developers spend most of their money. It's always a focus for customers as they're trying to think about cost. So, the provision of our continuous chromatography system, which is the world's first at process factory level scale, 2000 litre capability, running in perfusion mode, has caused a lot of interest. Not only is it running in continuous and it's flexible in that way, but you can use seven times less protein A than in traditional batch column, which translates into a huge amount of savings.

So, if I was to highlight a single technology within our continuous play I would mention continuous chromatography. We've also won numerous awards for other positions in technology for downstream bioprocessing in the continuous mode. We recently won the 2017 Aspen Award for the Advancement of Downstream Bioprocessing for Cadence™ BioSMB Process Systems (continuous chromatography systems).

We’ve also won awards for our clarification technologies that can be done in a continuous mode as well – clarification directly out of the bioreactor. We are very pleased with, not only the progress we have made updating our technologies, like the Cadence™ BioSMB Process Systems, but also the recognition we have received from our industry peers. This acknowledgement indicates that what Pall is producing is innovative and solving a problem. The act of R&D and new product development is long and complex, to get that recognition is truly motivating.

Thank you so much for the conversation. As you can tell, I’m incredibly excited about what the future holds for Pall and the impact continuous bioprocessing will have on our customers’ ability to deliver products that will have an enormous impact on their patients’ lives—in a way that is more efficient and less expensive than the current means.

Martin Smith was speaking to Laura Elizabeth Mason, Science Writer at Technology Networks.